2022 AD Strategic Fund: APOE Biology in Alzheimer's (ABA) (ABA)

Investigating the Protective Mechanisms of APOE2

How might certain gene variations increase protection against developing Alzheimer’s?

David Adam Brafman, Ph.D.
Arizona State University
Tempe, AZ - United States

Background

The apolipoprotein E (APOE) gene provides instructions for making the ApoE protein that is thought to help carry fats throughout the body. There are several variations of the APOE gene, including APOE-e2, APOE-e3 and APOE-e4. The APOE-e2 genetic variation is thought to reduce risk of Alzheimer’s in some populations. Although APOE-e2 appears to be protective, researchers know very little about how this genetic variation may impact biological brain changes associated with Alzheimer’s.

In Alzheimer’s, the proteins beta-amyloid and tau accumulate to form plaques and tangles respectively, two hallmark brain changes observed in the disease. Beta-amyloid plaques may hinder nerve cell communication in the brain and may contribute to brain cell death. Nerve cells in the brain produce beta-amyloid by processing the amyloid precursor protein (APP). Specialized types of brain cells called astrocytes and microglia are involved in the breakdown and removal of APP from the brain. An imbalance in these processes may contribute to the accumulation of beta-amyloid observed in Alzheimer’s.

In previous research, Dr. David Brafman and colleagues demonstrated that the protective effect from APOE-e2 may be related to contributions from astrocytes and microglia that impact APP processing. However, a complete understanding of how different forms of APOE, in particular APOE-e2, impact various aspects of APP processing is still lacking.

Research Plan

Dr. Brafman and colleagues will build on their earlier research to study the mechanisms to better understand how APOE-e2 impacts the build-up of beta-amyloid through APP processing. The researchers will study a specialized type of stem cell collected from adult human tissue called human induced pluripotent stem cells (hiPSCs). These are adult human skin cells that can be “reprogrammed” into any type of cell in the human body and grown in laboratory dishes. Using cells from individuals with Alzheimer’s and cognitively unimpaired individuals, the researchers will create nerve cells, microglia, and astrocytes with different APOE variations (i.e., APOE-e2, APOE-e3, APOE-e4). Dr. Brafman and colleagues will study how different forms of the APOE gene impact various points of APP processing in nerve cells, microglia, and astrocytes grown in laboratory dishes.

Impact

The findings may contribute to our understanding of the role of APOE-e2 in protecting individuals against Alzheimer’s risk. Results from the study may shed light on how this genetic change impacts biological brain changes associated with Alzheimer’s.